The molecular basis of all cancers is the accumulation of heritable genetic and epigenetic changes that result in loss of function of tumor suppressors and/or the inappropriate activation of proto-oncogenes. At the time of the last review, UVa and the Cancer Center had several investigators among its ranks who worked on various aspects of gene expression, replication, and genetic instability. However, a need was appreciated for a stronger representation of such programs within the Cancer Center and for a formal mechanism to foster intellectual exchange and collaborations. The Molecular Genetics Program was initiated to facilitate the focused, interactive, study of chromatin architecture, transcription, replication, mutation, repair, and cellular checkpoints. The long-range goals of this group are to understand the molecular mechanisms that underlie genetic and epigenetic defects in cancer. This new Program currently consists of 24 active investigators from 7 different departments, 13 of whom derived from other Programs in the Center and 11 of whom were recruited to UVa since the last renewal. Total extramural funding for the Molecular Genetics Program exceeds $9 million, including $2.6 million from the NCI and $550K from ACS or cancer-targeted DOD awards. This diverse but cohesive group meets monthly to hear presentations by its own members or by investigators in other relevant Programs. In the last two years, this monthly forum has also hosted four mini-symposia focused on particular cancers. A research retreat off-site provides a venue for short platform talks and posters, thus keeping the group abreast of the research progress of the other members of the Molecular Genetics Program in a comprehensive way on a yearly basis. The group's members have also organized six symposia hosting outside speakers on topics relevant to cancer genetics and epigenetics. These activities have stimulated creative and informed thinking on the cancer problem, and have provided the framework for many productive collaborations among Cancer Center members. The goals of the Program are to develop comprehensive molecular models for the origins of genetic and epigenetic instability in cancer and to help uncover novel genes responsible for the development of neoplasms in diverse tumor types. In the short history of this Program, it has fostered several studies leading to the identification of therapeutic targets and more rational approaches to cancer therapy. The many activities and interactions have led directly or indirectly to 343 publications, of which 31% were inter-programmatic publications and 9% were intra-programmatic publications since the last renewal. In addition, Program members participate in 12 multi-investigator or collaborative NIH research awards including 8 from the NCI.